We have recently identified an epithelial gd T cell specific costimulatory molecule, junctional adhesion molecule-like protein (JAML). Binding of JAML to its ligand Coxsackie and Adenovirus receptor (CAR) provides costimulation leading to cellular proliferation and cytokine and growth factor production. Inhibition of JAML costimulation leads to diminished gd T cell activation and delayed wound closure similar to that seen in the absence of gd T cells. We hypothesize that JAML-CAR interactions play key roles in tissue homeostasis and that JAML-CAR expression and function are dysregulated in patients with chronic wounds. Interestingly, epidermal gd T cells are functionally unresponsive in both mice and patients with chronic wounds. Lack of costimulation through JAML may lead to T cell anergy resulting in defective T cell contributions to healing. If responsible, JAML and CAR molecules would then be possible targets for therapeutic interventions to accelerate wound healing. Prior to development of clinical applications, it is essential to determine how JAML- CAR interactions contribute to gd T cell activation and learn more about mechanisms that regulate functions of these molecules. We will identify mechanisms by which JAML-CAR interactions costimulate DETC. We will determine if there is a requirement for JAML-CAR interactions during homeostasis in murine skin and if defects in JAML signaling contribute to the T cell unresponsiveness seen in chronic wounds. We will examine the contributions of JAML-CAR interactions to human epidermal gd T cell functions and determine if expression is dysregulated in chronic wounds. Strategies will be employed to modulate JAML-CAR expression to accelerate wound healing in mouse models and human chronic wounds. Together, information gained in this study will contribute to development of a new paradigm for epithelial gd T cell activation and identify mechanisms and strategies for targeting the JAML-CAR costimulatory pathway to improve healing of chronic wounds. PUBLIC HEALTH RELEVANCE: We have identified JAML as an epithelial gd T cell specific costimulatory molecule. Epithelial gd T cells play important roles in tissue homeostasis and repair. New strategies for JAML costimulation of T cells for immunotherapy could have major benefits for healing of chronic wounds as well as impact treatment of asthma, inflammatory bowel disease and epithelial tumors.